Trisubstituted thiophenes as progesterone receptor modulators

ABSTRACT

The present invention is directed to novel trisubstituted thiophene derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by agonists and antagonists of the progesterone receptor. The clinical usage of these compounds are related to hormonal contraception, the treatment and/or prevention of secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate. Additional uses of the invention include stimulation of food intake.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/622,581, filed Oct. 27, 2004, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel trisubstituted thiophenederivatives, pharmaceutical compositions containing them and their usein the treatment or prevention of disorders and diseases mediated byagonists and antagonists of the progesterone receptors. The clinicalusage of these compounds are related to hormonal contraception, thetreatment and/or prevention of secondary dysmenorrhea, amenorrhea,dysfunctional uterine bleeding, uterine leiomyomata, endometriosis;polycystic ovary syndrome, carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate. Additional uses of theinvention include stimulation of food intake.

BACKGROUND OF THE INVENTION

Intracellular receptors are a class of structurally related proteinsinvolved in the regulation of gene proteins. Steroid receptors are asubset of these receptors, including the progesterone receptors (PR),androgen receptors (AR), estrogen receptors (ER), glucocorticoidreceptors (GR) and mineralocorticoid receptors (MR). Regulation of agene by such factors requires the intracellular receptor and acorresponding ligand which has the ability to selectively bind to thereceptor in a way that affects gene transcription.

Progesterone receptor modulators (progestagens) are known to play animportant role in mammalian development and homeostasis. Progesterone isknown to be required for mammary gland development, ovulation and themaintenance of pregnancy. Currently, steroidal progestin agonists andantagonists are clinically approved for contraception, hormonereplacement therapy (HRT) and therapeutic abortion. Moreover, there isgood preclinical and clinical evidence for the value of progestinantagonists in treating endometriosis, uterine leiomyomata (fibroids),dysfunctional uterine bleeding and breast cancer.

The current steroidal progestagens have been proven to be quite safe andare well tolerated. Sometimes, however, side effects (e.g. breasttenderness, headaches, depression and weight gain) have been reportedthat are attributed to these steroidal progestagens, either alone or incombination with estrogenic compounds.

Steroidal ligands for one receptor often show cross-reactivity withother steroidal receptors. As an example, many progestagens also bind toglucocorticoid receptor. Non-steroidal progestagens have no molecularsimilarity with steroids and therefore one might also expect differencesin physicochemical properities, pharmacokinetic (PK) parameters, tissuedistribution (e.g. CNS versus peripheral) and, more importantly,non-steroidal progestagens may show no/less cross-reactivity to othersteroid receptors. Therefore, non-steroidal progestagens will likelyemerge as major players in reproductive pharmacology in the foreseeablefuture.

It was known that progesterone receptor existed as two isoforms,full-length progesterone receptor isoform (PR-B) and its shortercounterpart (PR-A). Recently, extensive studies have been implemented onthe progesterone receptor knockout mouse (PRKO, lacking both the A- andB-forms of the receptors), the mouse knockoutting specifically for thePR-A isoform (PRAKO) and the PR-B isoform (PRBKO). Different phenotypeswere discovered for PRKO, PRAKO and PRBKO in physiology studies in termsof fertility, ovulation uterine receptivity, uterine proliferation,proliferation of mammary gland, sexual receptivity in female mice,sexual activity in male mice and infanticide tendencies in male mice.These findings provided insights for synthetic chemists to construct notonly selective progesterone receptor modulator (SPRM), but also PR-A orPR-B selective progesterone receptor modulator.

SUMMARY OF THE INVENTION

The present invention provides novel trisubstituted thiophenes offormula (I):

wherein

R₁ and R₂ are independently selected from the group consisting ofhydrogen, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl andheteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl orheteroaryl-alkyl group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, alkyl, alkoxy, —S(alkyl), —SO₂R^(C), NO₂, CN, CO₂H,R^(C), —OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR and CF₃;

wherein R^(C) is selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;

wherein Q is selected from the group consisting of O, S, NH, N(alkyl)and —CH═CH—;

wherein R^(D) and R^(E) are each independently selected from the groupconsisting of hydrogen and alkyl; alternatively R^(D) and R^(E) aretaken together with the nitrogen atom to which they are bound to form a4 to 8 membered ring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro, CF₃ or cyano;

wherein R^(F) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, CF₃ nitro or cyano;

alternatively, R₁ and R₂ are taken together with the carbon atom towhich they are bound to form C(O), or to form a cycloalkyl orhetero-cycloalkyl.

R₃ is aryl or heteroaryl, optionally substituted by up to three of R⁵;wherein

R₅ is independently selected from the group consisting of halogen,hydroxy, R^(C), amino, alkylamino, dialkylamino, nitro, cyano, CF₃,SO₂(alkyl), —C(O)R^(G), —C(O)OR^(G), —OC(O)R^(G), —OC(O)OR^(G),—OC(O)N(R^(G))₂, —N(R^(G))C(O)R^(G), —OSi(R^(G))₃—OR^(G), —SO₂N(R^(G))₂,—O-(alkyl)₁₋₄-C(O)R^(G) and —O-(alkyl)₁₋₄-C(O)OR^(G);

wherein each R^(G) is independently selected from hydrogen, alkyl, aryl,aralkyl; wherein the alkyl, aryl or aralkyl group is optionallysubstituted with one or more substituents independently selected fromalkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano,—OC(O)-alkyl or —C(O)O-alkyl;

alternatively two R^(G) groups are taken together with the nitrogen atomto which they are bound to form a heterocycloalkyl group; wherein theheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R₄ is alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl areoptionally substituted with up to three R₅;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention isprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby one or more progesterone receptors in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

Illustrating the invention is a method of contraception comprisingadministering to a subject in need thereof co-therapy with atherapeutically effective amount of a compound of formula (I) with anestrogenic compound.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)dysfunctional bleeding, (b) endometriosis, (c) uterine leiomyomata, (d)secondary amenorrhea, (e) polycystic ovary syndrome, (f) carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate, (g)stimulation of food intake in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I):

wherein R₁, R₂, R₃ and R₄ are as herein defined, useful for thetreatment of disorders mediated by progesterone receptors. Moreparticularly, the compounds of the present invention are useful for thetreatment and prevention of disorders mediated by the progesterone-A andprogesterone-B receptors. More preferably, the compounds of the presentinvention are tissue selective progesterone receptor modulators.

The progesterone receptor antagonists of this invention, used alone orin combination with an estrogenic compound, can be utilized in methodsof contraception and the treatment and/or prevention of benign andmalignant neoplastic disease. Specific uses of the compounds andpharmaceutical compositions of invention include the treatment and/orprevention of uterine myometrial fibroids, endometriosis, benignprostatic hypertrophy; carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate, pituitary, meningioma andother hormone-dependent tumors. Additional uses of the presentprogesterone receptor antagonists include the synchronization of theestrus in livestock.

The progesterone receptor agonists of this invention, used alone or incombination, can be utilized in methods of contraception and thetreatment and/or prevention of dysfunctional bleeding, uterineleiomyomata, endometriosis; polycystic ovary syndrome, carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate.Additional uses of the invention include stimulation of food intake.

In an embodiment of the invetion, R₁ and R₂ are taken together with thecarbon atom to which they are bound to form C(O), or to form acycloalkyl or hetero-cycloalkyl.

In another embodiment, R₃ is selected from the group consisting of aryl,thienyl and pyridinyl

In another embodiment, R₄ is substituted aryl.

In yet another embodiment of the present invention, R₄ is C₁₋₈ alkyl.

In an embodiment of the present invention are compounds of formula (I)wherein R₃ is 4-pyridinyland R₄ is aryl, heteroaryl, substituted aryl,substituted heteroaryl or C₁₋₄ alkyl.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, acetate, fumarate, gluceptate,gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

As used herein, the term “progestogen antagonist” shall includemifepristone, J-867 (Jenapharm/TAP Pharmaceuticals), J-956(Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-33628(Organon), ORG-31806 (Organon), onapristone and PRA248 (Wyeth).

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, includes straight and branchedchain compositions of one to eight carbon atoms. For example, alkylradicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “lower”when used with alkyl means a carbon chain composition of 1-4 carbonatoms. Similarly, the group “-(alkyl)₀₋₄-”, whether alone or as part ofa large substituent group, shall mean the absence of an alkyl group orthe presence of an alkyl group comprising one to four carbon atoms.Suitable examples include, but are not limited to —CH₂—, —CH₂CH₂—,CH₂—CH(CH₃)—, CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, CH₂CH₂CH₂CH₂—, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocyclic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. Suitable examples include benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, saturated ring system, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein, unless otherwise noted, the term “cycloalkyl-alkyl”shall mean any lower alkyl group substituted with a cycloalkyl group.Suitable examples include, but are not limited to cyclohexyl-methyl,cyclopentyl-methyl, cyclohexyl-ethyl, and the like.

As used herein, unless otherwise noted, the terms “acyloxy” shall mean aradical group of the formula —O—C(O)—R where R is alkyl, aryl oraralkyl, wherein the alkyl, aryl or aralkyl is optionally substituted.As used herein, the term “carboxylate” shall mean a radical group of theformula —C(O)O—R where R is alkyl, aryl or aralkyl, wherein the alkyl,aryl or aralkyl is optionally substituted.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

As used herein, unless otherwise noted, the term “heteroaryl-alkyl”shall mean any lower alkyl group substituted with a heteroaryl group.Suitable examples include, but are not limited to pyridyl-methyl,isoquinolinyl-methyl, thiazolyl-ethyl, furyl-ethyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl,chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and thelike.

As used herein, unless otherwise noted, the term“heterocycloalkyl-alkyl” shall mean any lower alkyl group substitutedwith a heterocycloalkyl group. Suitable examples include, but are notlimited to piperidinyl-methyl, piperazinyl-methyl, piperazinyl-ethyl,morpholinyl-methyl, and the like.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,heteroaryl, heterocycloalkyl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.Additionally when aralkyl, heteroaryl-alkyl, heterocycloalkyl-alkyl orcycloalkyl-alkyl group is substituted, the substituent(s) may be on anyportion of the group (i.e. the substituent(s) may be on the aryl,heteroaryl, heterocycloalkyl, cycloalkyl or the alkyl portion of thegroup.)

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

-   Ac=Acetyl group (—C(O)—CH₃)-   DCM=Dichloromethane-   DIPEA or DIEA Diisopropylethylamine-   DMAP=N,N-Dimethylaminopyridine-   DMF=Dimethyl formamide-   ERT=Estrogen replacement therapy-   Et=ethyl (i.e. —CH₂CH₃)-   EtOAc=Ethyl acetate-   FBS=Fetal bovine serum-   HPLC=High pressure liquid chromatography-   HRT=Hormone replacement therapy-   LHMDS or LiHMDS or=Lithium Hexamethyldisilazinamide-   (TMS)₂NLi or LiN(TMS)₂-   MeOH=Methanol-   Ph=Phenyl-   PPTS=Pyridinium p-toluenesulfonate-   TBAF=Tetra(n-butyl)ammonium fluoride-   TBDMS=Tert-butyldimethylsilane-   TBS=Tert-butyl-dimethyl-silyl-   TBSCl=Tert-butyl-dimethyl-silyl chloride-   pTEA or Et₃N=Triethylamine-   TFA=Trifluoroacetic acid-   THF=Tetrahydrofuran-   TMS=Trimethylsilyl-   TsOH=Tosic acid

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated. Wherein the present inventiondirected to co-therapy comprising administration of one or morecompound(s) of formula I and a progestogen or progestogen antagonist,“therapeutically effective amount” shall mean that amount of thecombination of agents taken together so that the combined effect elicitsthe desired biological or medicinal response. For example, thetherapeutically effective amount of co-therapy comprising administrationof a compound of formula I and progestogen would be the amount of thecompound of formula I and the amount of the progestogen that when takentogether or sequentially have a combined effect that is therapeuticallyeffective. Further, it will be recognized by one skilled in the art thatin the case of co-therapy with a therapeutically effective amount, as inthe example above, the amount of the compound of formula I and/or theamount of the progestogen or progestogen antagonist individually may ormay not be therapeutically effective.

As used herein, the term “co-therapy” shall mean treatment of a subjectin need thereof by administering one or more compounds of formula I witha progestogen or progestogen antagonist, wherein the compound(s) offormula I and progestogen or progestogen antagonist are administered byany suitable means, simultaneously, sequentially, separately or in asingle pharmaceutical formulation. Where the compound(s) of formula Iand the progestogen or progestogen antagonist are administered inseparate dosage forms, the number of dosages administered per day foreach compound may be the same or different. The compound(s) of formula Iand the progestogen or progestogen antagonist may be administered viathe same or different routes of administration. Examples of suitablemethods of administration include, but are not limited to, oral,intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal,and rectal. Compounds may also be administered directly to the nervoussystem including, but not limited to, intracerebral, intraventricular,intracerebroventricular, intrathecal, intracisternal, intraspinal and/orperi-spinal routes of administration by delivery via intracranial orintravertebral needles and/or catheters with or without pump devices.The compound(s) of formula I and the progestogen or progestogenantagonist may be administered according to simultaneous or alternatingregimens, at the same or different times during the course of thetherapy, concurrently in divided or single forms.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Compounds of formula (I) wherein R3 is 4-pyridyl, R4 is aryl and R1 andR2 is O may be prepared according to the processes outlined in Scheme 1.

More particularly, a suitably substituted compound of formula (II),where X and Y are O or S, a known compound or compound prepared by knownmethods, is reacted with a compound of formula (III), a known compound,in the presence of an organic acid such as acetic acid, p-TSA, oxalicacid and the

like, in an organic solvent such as THF, 1,4-dioxlane, ethyl ether, andthe like, at a temperature in the range of 0 to 25° C. to yield thecorresponding compound of formula (IV). The condensation of compound IIand III with sulfur to yield compound IV can be effected by variouscoupling reactions including Willgerodt-Kindler Reaction.

The compound of formula (IV) is reacted with a suitably substitutedcompound of formula (V), a known cyclic or normal secondary amine, inthe presence of HC(OEt)₃ or HC(OMe)₃ at a temperature in the range of 0to 250° C. to yield the corresponding compound of formula (VI).

Accordingly, the compound of formula (VI) is reacted with a suitablysubstituted bromoketone, in the presence of an organic base, such astriethyl amine, duisopropyl ethyl amine, pyridine and the like; orinorganic base, such as K₂CO₃, Na₂CO₃ and the like, in an organicsolvent such as MeOH, toluene, benzene, THF, methylene chloride, at anelevated temperature in the range of 25 to 150° C. to yield thecorresponding compound of formula (VII).

The compound of formula (VII) is deprotected to yield compound offormula (VIII) in the presence of organic protic acid, such as aceticacid, camphor sulfonic acid, p-TSA, oxalic acid and the like in anorganic solvent, such as acetone, THF, 1,4-dioxane and the like.

One skilled in the art will recognize that it may be necessary and/ordesirable to protect one or more of the R¹, R² and/or R³, R⁴ groups atany of the steps within the process described above. This may beaccomplished using known protecting groups and know protection andde-protection reagents and conditions, for example such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991.

TABLE 1

Structure Example # or II R MF 1 I 3,4-di-Cl- C₂₃H₂₀C₁₂N₂O₃S phenyl 2 I4-F-phenyl C₂₃H₂₁FN₂O₃S 3 I 4-Cl-phenyl C₂₃H₂₁ClN₂O₃S 4 I 4-NO₂-C₂₃H₂₁N₃O₅S phenyl 5 I Et C₁₉H₂₂N₂O₃S 6 I Phenyl C₂₃H₂₂N₂O₃S 7 I 3-MeO-C₂₄H₂₄N₂O₄S phenyl 8 I 3,5-di-CF₃- C₂₅H₂₀F₆N₂O₃S phenyl 9 I 2-MeO-C₂₄H₂₄N₂O₄S phenyl 10 I 3-Br-phenyl C₂₃H₂₁BrN₂O₃S 11 II PhenylC₂₁H₁₈N₂O₂S 12 II 3-MeO- C₂₂H₂₀N₂O₃S phenyl 13 II 4-F-phenylC₂₁H₁₇FN₂O₂S 14 II 3,5-di-CF₃- C₂₃H₁₆F₆N₂O₂S phenyl 15 II 2-MeO-C₂₂H₂₀N₂O₃S phenyl 16 II 4-Cl-phenyl C₂₁H₁₇ClN₂O₂S 17 II 4-NO₂-C₂₁H₁₇N₃O₄S phenyl 18 II Et C₁₇H₁₈N₂O₂S 19 II 3-NO₂- C₂₁H₁₇N₃O₄S phenyl20 II 3-Br-phenyl C₂₁H₁₇BrN₂O₂S

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include, but are not limited to, the following saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

This invention includes pharmaceutical compositions comprising one ormore compounds of this invention, preferably in combination with one ormore pharmaceutically acceptable carriers and/or excipients. Theinvention also includes methods of contraception and methods of treatingor preventing maladies associated with the progesterone receptor, themethods comprising administering to a mammal in need thereof apharmaceutically effective amount of one or more compounds as describedabove wherein R4 is alkyl, aryl, heteroary or alkylaryl groupl.

The progesterone receptor antagonists of this invention, used alone orin combination with estrogen or partial estrogen antagonist, can beutilized in methods of contraception and the treatment and/or preventionof benign and malignant neoplastic disease. Specific uses of thecompounds and pharmaceutical compositions of invention include thetreatment and/or prevention of uterine myometrial fibroids,endometriosis, benign prostatic hypertrophy; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate,pituitary, meningioma and other hormone-depent tumors. Additional usesof the present progesterone receptor antagonists include thesynchronization of the estrus in livestock.

When used in contraception the progesterone receptor antagonists of thecurrent invention may be used either alone in a continuousadministration of between 0.1 and 500 mg per day, or alternatively usedin a different regimen which would entail 2-4 days of treatment with theprogesterone receptor antagonist after 21 days of a progestin. In thisregimen between 0.1 and 500 mg daily doses of the progestin (e.g.levonorgestrel, trimegestone, gestodene, norethindrone acetate,norgestimate or cyproterone acetate) would be followed by between 0.1and 500 mg daily doses of the progesterone receptor antagonists of thecurrent invention.

The progesterone receptor agonists of this invention, used alone or incombination, can also be utilized in methods of contraception and thetreatment and/or prevention of dysfunctional bleeding, uterineleiomyomata, endometriosis; polycystic ovary syndrome, carcinomas andadenocarcimomas of the endometrium, ovary, breast, colon, prostate.Additional uses of the invention include stimulation of food intake.

When used in contraception the progesterone receptor agonists of thecurrent invention are preferably used in combination or sequentiallywith an estrogen agonist (e.g. ethinyl estradiao). The preferred dose ofthe progesterone receptor agonist is 0.01 mg and 500 mg per day.

This invention also includes pharmaceutical compositions comprising oneor more compounds described herein, preferably in combination with oneor more pharmaceutically acceptable carriers or excipients. When thecompounds are employed for the above utilities, they may be combinedwith one or more pharmaceutically acceptable carriers, or excipients,for example, solvents, diluents and the like and may be administeredorally in such forms as tablets, caplules, dispersible powders,granules, or suspensions containing, for example, from about 0.05 to 5%of suspending agent, syrups containing, for example, from about 10 to50% of sugar, and elixirs containing, for example, from 20 to 50%ethanol, and the like, or in the form of sterile injectable solutions orsuspensions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.01 to about 500 mg/kgof animal body weight, preferably given in dual doses two to four timesa day, or in a sustained release form. For most large mammals, the totaldaily dosage is from about 1 to 100 mg, preferably from about 2 to 80mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, imtramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oil, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxylpropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ofdispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

The following non-limiting examples illustrate preparation and use ofthe compounds of the invention.

EXAMPLE 1 A.1-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-2-pyridin-4-yl-ethanethione

1-Pyridin-4-yl-ethanone (12.1 g, 0.1 mole), sulfur (3.36 g, 0.105 mol)and 1,4-dioxa-8-aza-spiro[4.5]decane were mixed with p-toluene sulfonicacid (0.50 g, 2.8 mmole) and heated to 120° C. for 3 hours. The slurrywas poured into MeOH (50 mL). A bright yellow solid precipitated out.This was filtered and washed with another 20 mL of MeOH. The solid wasdried to provide the product (24 g, 86.3%). ¹H NMR (CD₃OD) δ 8.41 (m,2H), 7.42 (m, 2H), 4.35 (m, 4H), 3.91 (m, 4H), 3.78 (m, 2H), 1.80 (m,2H), 1.48 (m, 2H). MS (m/z): 279 (MH⁺).

B.1-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethione

1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethanethione (20g, 72 mmol), HC(OEt)₃ (21.3 g, 144 mol), morpholine (48 g, 55 mmol) wasstirred at 125° C. for 4 hours. The solvent and excess reagent weredistilled out at 100° C. under house vacumm. A yellow precipitate cameout. After 30 min at 0° C., the precipitate was collected and washedwith water (10 mL) and dried overnight under air suction to provide theproduct (20 g, 54%). ¹H NMR (CDCl₃) δ 8.32 (m, 2H), 7.02 (m, 2H), 6.40(s, 1H), 4.61 (m, 1H), 4.30 (m, 1H), 3.98 (m, 4H), 3.70 (m, 6H), 3.5 (s,4H), 3.20 (m, 2H), 2.10 (m, 1H), 1.80 (m, 2H). MS (m/z): 376 (MH⁺).

C.(3,4-Dichloro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanon

1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethione(75 mg, 0.020 mmol), 2-bromo-1-(3,4-dichloro-phenyl)-ethanone (67 mg,0.020 mmol) was stirred in MeOH (1 mL) with Et₃N (21 mg,0.02 ml) for 4hours at 65 ° C. This was diluted with EtOAc (20 mL) and washed withbrine three times. The residue was purified by a preparative silica gelplate (5% MeOH/CH₂Cl₂) to provide product as a yellow solid (33 mg,35%). ¹H NMR (CDCl₃) δ 8.6 (m, 2H), 7.81 (s, 1H), 7.61-7.47 (m, 5H),3.72 (m, 3.56 (m, 3H), 3.52 (s, 4H), 3.41 (m, 1H), 3.23 (m, 4H), 1.82(m, 4H). MS (m/z): 475 (MH⁺).

EXAMPLE 2[5-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-fluoro-phenyl)-methanone

The title product was prepared in 33% yield according to the proceduredescribed in Example 1c using1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethioneand 2-bromo-1-(4-fluoro-phenyl)-ethanone as starting material. ¹H NMR(CDCl₃) δ 8.61 (dd, J=1.5 and 4.6 Hz, 5 2H), 7.86-7.83 (m, 2H),7.53-7.50 (m, 3H), 7.20-7.15 (m, 2H), 3.98 (s, 4H), 3.23 (t, J=5.7 Hz,4H), 1.83 (t, J=5.7 Hz, 4H); MS (m/z): 425 (MH⁺).

EXAMPLE 3 (4-Chloro-phenyl)-[5-(14-dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone

The title product was prepared in 29% yield according to the proceduredescribed in Example 1c using1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethione(374.5 mg, 1 mmol), 2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1mmol) as starting material. ¹H NMR (CDCl₃) δ 8.62-8.58 (m, 2H),7.78-7.74 (m, 2H), 7.52-7.45 (m, 5H), 3.98 (s, 1H), 3.24 (t, J=5.7 Hz,4H), 1.83 (t, J=5.8 Hz, 4H); MS (m/z): 441 (MH⁺); HRMS: calc'd MH⁺ forC₂₃H₂₁ClN₂O₃S 441.1039; found 441.1025.

EXAMPLE 4 [5-(14-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-nitro-phenyl)-methanone

The title product was prepared in 18% yield according to the proceduredescribed in Example 1c using1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethione(374.5 mg, 1 mmol), 2-bromo-1-(4-nitro-phenyl)-ethanone (244 mg, 1 mmol)as starting material. ¹H NMR (CDCl₃) δ 8.61 (dd, J=1.6 and 4.5 Hz, 2H),8.36-8.33 (m, 2H), 7.95-7.92 (m, 2H), 7.47-7.46 (m, 3H), 3.99 (s, 4H),3.27 (t, J=5.7 Hz, 4H), 1.83 (t, J=5.7 Hz, 4H); MZ (m/e): 452 (MH⁺).HRMS: calc'd MH⁺ for C₂₃H₂₁N₃O₅S 452.1280. Found 452.1286

EXAMPLE 51-[5-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-1-one

The title product was prepared in 22% yield as a white solid accordingto the procedure described in Example 1c using1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propenethione(374.5 mg, 1 mmol), 1-bromo-butan-2-one (90%, 0.11 mL, 1 mmol) asstarting material. ¹H NMR (CDCl₃) δ 8.62 (dd, J=1.5 and 4.6 Hz, 2H),7.65 (s,1H), 7.55 (dd, J=1.5 and 4.6 Hz, 2H), 3.97 (s, 4H), 3.17 (t,J=5.7 Hz, 4H), 2.85 (q, J=7.4 Hz, 2H), 1.82 (t, J=5.7 Hz, 4H), 1.23 (t,J=7.4 Hz, 3H). MS (m/z): 359 (MH⁺); HRMS: Calc'd MH+for C₁₉H₂₂N₂O₃S359.1429. Found 359.1420

EXAMPLE 6[5-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-phenyl-methanone

The title product was prepared in 28% yield as a yellow solid accordingto the procedure described in Example 1c using 2-bromo-1-phenyl-ethanoneas starting material. ¹H NMR (CDCl₃) δ 8.56 (m, 2H), 7.75 (m, 2H), 7.5(m, 6H), 4.01 (s, 4H), 3.23 (m, 4H), 1.88 (m, 4H); MS (m/z): 407 (MH⁺);HRMS: Calc'd MH⁺ for C₂₃H₂₂N₂O₃S 407.1429. Found 407.1436.

EXAMPLE 7[5-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl-](3-methoxy-phenyl)-methanone

The title product was prepared in 24% yield as a yellow solid accordingto the procedure described in Example 1 c using2-bromo-1-(3-methoxy-phenyl)-ethanone as starting material. ¹H NMR(CDCl₃) δ 8.65 (m, 2H), 7.59-7.10(m, 7H), 3.95 (s, 4H), 3.25 (m, 4H),1.82 (m, 4H); MS (m/z): 437 (MH⁺); HRMS: calc'd MH⁺ for C₂₄H₂₄N₂O₄S437.1535. Found 437.1534.

EXAMPLE 8 (3,5-Bis-trifluoromethyl-phenyl)-[5-(14-dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone

The title product was prepared in 18% yield according to the proceduredescribed in Example 1c using1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-ethanone as startingmaterial. ¹H NMR (CDCl₃) δ 8.60-7.39 (m, 7H), 3.95 (s, 4H), 3.28 (m,4H), 1.82 (m, 4H); MS (m/z): 543 (MH⁺); HRMS: calc'd MH⁺ forC₂₅H₂₀F₆N₂O₃S 543.1177; found 543.1157.

EXAMPLE 9[5-(1,4-Dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(2-methoxy-phenyl)-methanone

The title product was prepared in 23% yield according to the proceduredescribed in Example 1c using 1-(2-methoxy-phenyl)-2-bromo-ethanone asstarting material. ¹H NMR (CDCl₃) δ 8.55 (m, 2H), 7.45-7.30(m, 7H), 6.95(m, 2H), 3.95 (s, 4H), 3.21 (m, 4H), 1.81 (m, 4H); MS (m/z): 437 (MH⁺);HRMS: calc'd MH⁺ for C₂₄H₂₄N₂O₄S 437.1535; found 437.1541.

EXAMPLE 10(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]-dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone

The title product was prepared in 25% yield according to the proceduredescribed in Example 1c using1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-ethanone as startingmaterial. ¹H NMR (CDCl₃) δ 8.61 (m, 2H), 7.91-7.31 (m, 7H), 3.94 (s,4H), 3.23 (m, 4H), 1.81 (m, 4H); MS (m/z): 485, 487 (MH⁺); HRMS: calc'dMH⁺ for C₂₃H₂₁BrN₂O₃S 485.0534. Found 485.0514.

EXAMPLE 11 1-(5-Benzoyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one

A solution of[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-phenyl-methanone(39.5 mg, 0.097 mmole), p-toluenesulfonic acid monohydrate (37 mg, 0.194mmole, 2 eq.), acetone (2 mL), and water (1 mL) was heated to refluxovernight. The solution was diluted with water and made basic to pH 14with 4N sodium hydroxide or 1 M sodium carbonate solution. The solutionwas extracted twice with ethyl acetate. The organic extracts were driedover magnesium sulfate, filtered, and purified by column chromatographyto provide the product as yellow solid (22 mg, 63%). ¹H NMR (CDCl₃) δ8.61 (m, 2H), 7.81-7.45 (m, 8H), 3.46 (m, 4H), 2.52 (m, 4H). MS (m/z):363 (MH⁺), 385 (MNa⁺).

EXAMPLE 121-[5-(3-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 73% yield according to the proceduredescribed in Example 11 using[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3-methoxy-phenyl)-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.65 (m, 2H), 7.51-7.12 (m, 9H),3.42 (m, 4H), 2.62 (m, 4H); Ms (m/z): 393 (MH⁺), 391 (MH⁻); HRMS: calc'dMH⁺ for C₂₂H₂₀N₂O₃S 393.1273. Found 393.1280.

EXAMPLE 131-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 69% yield according to the proceduredescribed in Example 11 using[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-fluoro-phenyl)-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.62-7.11 (m, 9H), 3.42 (m, 4H),2.61 (m, 4H); MS (m/z): 413 (MNa⁺), 379 (MH⁻); HRMS: calc'd MH⁺ forC₂₁H₁₇FN₂O₂S 381.1073. Found 381.1080.

EXAMPLE 141-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 33% yield as a yellow solid accordingto the procedure described in Example 11 using(3,5-bis-trifluoromethyl-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.65-7.42 (m, 8H), 3.51 (m, 4H),2.61 (m, 4H); MS (m/z): 499 (MH⁺), 497 (MH⁻).

EXAMPLE 151-[5-(2-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 48% yield as a yellow solid accordingto the procedure described in Example 11 using(2-methoxy-phenyl)-[5-(1,44-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.62-6.97 (m, 9H), 3.80 (s, 3H),3.42 (m, 4H), 2.58 (m, 4H); MS (m/z): 393 (MH⁺), 391 (MH⁻); HRMS: calc'dMH⁺ for C₂₂H₂₀N₂O₃S 393.1273. Found 393.1289.

EXAMPLE 161-[5-(4-Chloro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 74% yield according to the proceduredescribed in Example 11 using(4-chloro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.65-7.40 (m, 9H), 3.41 (m, 4H),2.59 (m, 4H). Ms (m/z): 397 (MH⁺), 395 (MH⁻); HRMS: calc'd MH+forC₂₁H₁₇ClN₂O₂S 397.0777. Found 397.0767.

Anal. calc'd for C₂₁H₁₇ClN₂O₂S, C, 63.55%; H, 4.32%; N, 7.06%. Found, C,63.29%; H, 4.20%; N, 7.06%.

EXAMPLE 17 1-[5-(4-Nitro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 47% yield as a yellow solid accordingto the procedure described in Example 11 using(4-nitro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.65-6.97 (m, 9H), 3.24 (m, 4H),2.60 (m, 4H). Ms (m/z): 408 (MH⁺), 407 (MH⁻); HRMS: calc'd MH⁺ forC₂₁H₁₇N₃O₄S 408.1018. Found 408.1024.

EXAMPLE 18 1-(5-Propionyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one

The title product was prepared in 60% yield as a white solid accordingto the procedure described in Example 11 using1-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-propan-1-oneas starting material. ¹H NMR (CDCl₃) δ 8.68 (m, 2H), 7.55 (m, 2H), 3.41(m, 4H), 2.91 (m, 2H), 2.56 (m, 2H), 1.24 (m, 3H). Ms (m/z): 315 (MH⁺),313 (MH⁻); HRMS: calc'd MH⁺ for C₁₇H₁₈N₂O₂S 315.1167. Found 315.1171.

Anal. calc'd for C₁₇H₁₈N₂O₂S, C, 64.94%; H, 5.77%; N, 8.91%. Found, C,64.16%; H, 5.77%; N, 8.52%.

EXAMPLE 191-[5-(3-Bromo-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in % yield according to the proceduredescribed in Example 11 using(3-bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material.

HRMS: calc'd MH⁺ for C₂₁H₁₇N₃O₄S 408.1018. Found 408.1028.

EXAMPLE 201-[5-(3-Bromo-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one

The title product was prepared in 71% yield according to the proceduredescribed in Example 11 using(3-bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanoneas starting material. ¹H NMR (CDCl₃) δ 8.68 (m, 2H), 7.92-7.35 (m, 7H),3.43 (m, 4H), 2.61 (m, 2H). Ms (m/z): 441 (MH⁺), 439 (MH⁻); HRMS: calc'dMH⁺ for C₂₁H₁₇BrN₂O₂S 441.0272. Found 441.0263.

Anal. calc'd for C₂₁H₁₇BrN_(z)O₂S, C, 57.15%; H, 3.88%; N, 6.35%. Found,C, 57.48%; H, 3.93%; N, 5.97%.

EXAMPLE 21 In Vitro Test

T47D human breast cancer cells are grown in RPMI medium without phenolred (Invitrogen) containing 10% (v/v) heat-inactivated fetal bovineserum (FBS; Hyclone), 1% (v/v) penicillin-streptomycin (Invitrogen), 1%(w/v) glutamine (Invitrogen), and 10 mg/mL insulin (Sigma). Incubationconditions are 37° C. in a humidified 5% (v/v) carbon dioxideenvironment. For assay, the cells are plated in 96-well tissue cultureplates at 10,000 cells per well in assay medium [RPMI medium withoutphenol red (Invitrogen) containing 5% (v/v) charcoal-treated FBS(Hyclone) and 1% (v/v) penicillin-streptomycin (Invitrogen)]. Two dayslater, the medium is decanted and the compounds are added in a finalconcentration of 0.1% (v/v) dimethyl sulfoxide in fresh assay medium.Twenty-four hours later, an alkaline phosphatase assay is performedusing a SEAP kit (BD Biosciences Clontech, Palo Alto, Calif.). Briefly,the medium is decanted and the cells are fixed for 30 minutes at roomtemperature with 5% (v/v) formalin (Sigma). The cells are washed oncewith room temperature Hank's buffered saline solution (Invitrogen).Equal volumes (0.05 mL) of 1× Dilution Buffer, Assay Buffer and 1:20substrate/enhancer mixture are added. After 1-hour incubation at roomtemperature in the dark, the lysate is transferred to a white 96-wellplate (Dynex) and luminescence is read using a LuminoSkan Ascent (ThermoElectron, Woburn, Mass.).

TABLE 2

Example # Structure (I or II) R % inhibition 1 I 3,4-di-Cl-phenyl 6 2 I4-F-phenyl 15 3 I 4-Cl-phenyl 27 4 I 4-NO₂-phenyl 0 5 I Et 0 6 I Phenyl34 7 I 3-MeO-phenyl 42 8 I 3,5-di-CF₃-phenyl 0 9 I 2-MeO-phenyl 30 10 I3-Br-phenyl 42 11 II Phenyl 35 12 II 3-MeO-phenyl 24 13 II 4-F-phenyl 4614 II 3,5-di-CF₃-phenyl 57 15 II 2-MeO-phenyl 39 16 II 4-Cl-phenyl 30 17II 4-NO₂-phenyl 30 18 II Et 26 19 II 3-NO₂-phenyl 29 20 II 3-Br-phenyl23

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (I):

wherein R₁ and R₂ are connected together with the carbon atom to whichthey are bound via a—O(CH₂)₂O— linker to form a ring, R₁ and R₂ areconnected together with the carbon atom to which they are bound to formC(O); R₃ is aryl or pyridinyl, optionally substituted by up to three ofR₅; R₄ is selected from the group consisting of CH₃CH₂—, CH₃CH(CH₃),CH₃CH₂CH₂—, aryl and pyridinyl, wherein the aryl or pyridinyl isoptionally substituted by up to three of R₅; wherein R₅ is selected fromthe group consisting of halogen, CF₃, MeO, NO₂ and CN; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1selected from the group consisting of[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3-methoxy-phenyl)-methanone;(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone;1-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one;1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one;and1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one.3. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.